Methods and Compositions For The Prevention and Treatment of Kidney Disease

ABSTRACT

The invention provides compositions for preventing or treating kidney disease and improving kidney function comprising at least two ingredients selected from the group consisting of antioxidants and mitochondrial cofactors in amounts sufficient for preventing or treating kidney disease or for improving kidney function and methods for preventing and treating kidney disease or improving kidney function comprising administering such compositions to an animal susceptible to or suffering from kidney disease or impaired kidney function. In a preferred embodiment, the composition is admixed with one or more food ingredients to produce a food composition useful for preventing or treating kidney disease and improving kidney function, particularly in senior animals.

This application claims priority to U.S. Provisional Application Ser.No. 60/709,071 filed Aug. 17, 2005, the disclosure of which isincorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates generally to compositions and methods forcombating kidney disease and improving kidney function and particularlyto the use of food compositions for preventing and treating kidneydisease and improving kidney function.

2. Description of the Prior Art

It has been postulated since 1956 that the production of active oxygenspecies or free radicals during aerobic respiration results in oxidativedamage that hastens aging and death in animals (Beckman, K., et al.,“The Free Radical Theory of Aging Matures,” Phys. Rev., 78: 547-581(1998)). Active oxygen species cause aging through various mechanisms,including directly damaging cellular DNA (Cutler, R., “Antioxidants andaging”, Am. J. Clin. Nutr., 53: 373S-379S (1991) and lipids and proteins(Tylicki, L., et al. “Antioxidants: A Possible Role in KidneyProtection,” Kid. Bl. Press. Res., 26: 303-314 (2003)). Free radicals,often produced in the mitochondria, where aerobic respiration occurs,damage mitochondrial DNA, proteins, and lipids, e.g., U.S. Patent App.Pub. No. US 2003/0060503.

It has also been postulated that active oxygen species may play a rolein causing kidney disease (Ongajooth L., et al. “Role of LipidPeroxidation, Trace Elements and Antioxidant Enzymes in Chronic RenalDisease Patients,” J. Med. Assc. Thai., 79:791-800 (1996)). Severalmechanisms have been proposed to account for this increase in renalfailure, e.g., Hasselwander, et al. “Oxidative Stress in Chronic RenalFailure,” Free Rad. Res. 29:1-11 (1998), Shah, S., “The Role of ReactiveOxygen Metabolites in Glomerular Disease,” Annu. Rev. Physiol.,57:245-62 (1995)), but scientific studies to date are inconclusiveregarding whether antioxidant treatment is beneficial to those withkidney disease. Some studies indicate that there is a role for variousantioxidant supplementations in the protection against kidney disease,e.g., Kedziora-Kornatowska et al, “Effect of Vitamin E and Vitamin CSupplementation on Antioxidative State and Renal Glomerular BasementMembrane Thickness in Diabetic Kidney”, Nephron Exp. Nephrol.,95:e134-e143 (2003). Other studies note the potential pro-oxidantproperties of antioxidant supplements, concluding that there is not yetenough experimental evidence to recommend antioxidant supplements toalleviate kidney disease, e.g., Tylicki.

However, despite years of studies and developments relating to kidneydisease and renal function, kidney disease and poor renal functionremain a major health problem. There is, therefore, a need for newmethods and compositions for preventing and treating kidney disease andfor improving kidney function.

SUMMARY OF THE INVENTION

It is, therefore, an object of the present invention to providecompositions and methods for preventing and treating kidney disease.

It is another object of the present invention to provide compositionsand methods for improving kidney function.

It is a further object of the invention to provide methods forpreventing and treating kidney disease and for improving kidney functionin senior animals.

It is another object of the invention to provide food compositions forpreventing and treating kidney disease.

It is another object of the invention to provide articles of manufacturein the form of kits that contain combinations of compositions anddevices useful for preventing and treating kidney disease.

It is a further object of the invention to decrease the morbidity andmortality caused by kidney disease.

These and other objects are achieved using a novel compositions andmethods for preventing or treating kidney disease and for improvingkidney function. The compositions comprise at least two ingredientsselected from the group consisting of antioxidants and mitochondrialcofactors in amounts sufficient for preventing or treating kidneydisease or to improve kidney function. Food compositions comprising oneor more food ingredients and the compositions are preferred. The methodscomprise administering such compositions to animals susceptible to orsuffering from kidney disease or administering the compositions toanimals experiencing a decline in kidney function, particularly adecline due to aging. Kits comprising the composition components (atleast two of an antioxidant and/or mitochondrial cofactor) and one ormore optional feed ingredients and renal drugs are also provided.

Other and further objects, features and advantages of the presentinvention will be readily apparent to those skilled in the art.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The term “animal” means a human or other animal likely to develop orsuffering from kidney disease or a decline in kidney function(particularly due to aging), including avian, bovine, canine, equine,feline, hicrine, murine, ovine, and porcine animals. Preferably, theanimal is a canine or feline.

The term “renal drug” means any compound, composition, or drug usefulfor preventing or treating kidney disease.

The term “in conjunction” means that one or more of the compositions andcompounds (e.g., renal drugs or composition components) of the presentinvention are administered to an animal (1) together in a foodcomposition or (2) separately at the same or different frequency usingthe same or different administration routes at about the same time orperiodically. “Periodically” means that the compositions, foodcompositions, and compounds are administered on a dosage scheduleacceptable for a specific composition, food composition, and compoundand that the food compositions are administered or fed to an animalroutinely as appropriate for the particular animal. “About the sametime” generally means that the compositions, composition components,renal drugs, and food compositions are administered at the same time orwithin about 72 hours of each other. In conjunction specificallyincludes administration schemes wherein renal drugs are administered fora prescribed period and the compositions are administered indefinitely.

The term “companion animal” means an individual animal of any specieskept by a human caregiver as a pet or any individual animal of a varietyof species that have been widely domesticated as pets, including dogs(Canis familiaris) and cats (Felis domesticus), whether or not theindividual animal is kept solely or partly for companionship.

The term “senior” refers to a life-stage of an animal. For small andregular breed canines, as well as for felines, the “senior” stage startsat about age 7. For large breed canines (a canine that weighs more than50 pounds (22.7 kg) as an adult), the “senior” stage starts at about age5.

The term “improve kidney function” means that a composition isadministered to or a method is used for an animal for a period effectiveto improve kidney function as determined by comparison with kidneyfunction in animals not being administered the composition or using themethod.

The term “antioxidant” means a substance capable of reacting with andneutralizing free radicals. Examples of such substances includebeta-carotene, selenium, coenzyme Q10 (ubiquinone), lutein,tocotrienols, soy isoflavones, S-adenosylmethionine, glutathione,N-acetylcysteine, vitamin E, vitamin C, and α-lipoic acid. Examples offoods containing useful levels of one or more antioxidants include butare not limited to ginkgo biloba, green tea, broccoli, citrus pulp,grape pomace, tomato pomace, carrot, spinach, and a wide variety offruit and vegetable meals.

This invention is not limited to the particular methodology, protocols,and reagents described herein because they may vary. Further, theterminology used herein is for the purpose of describing particularembodiments only and is not intended to limit the scope of the presentinvention. As used herein and in the appended claims, the singular forms“a,” “an,” and “the” include plural reference unless the context clearlydictates otherwise, e.g., reference to “a host cell” includes aplurality of such host cells.

Unless defined otherwise, all technical and scientific terms and anyacronyms used herein have the same meanings as commonly understood byone of ordinary skill in the art in the field of the invention. Althoughany methods and materials similar or equivalent to those describedherein can be used in the practice of the present invention, thepreferred methods, devices, and materials are described herein.

All patents, patent application, and publications mentioned herein areincorporated herein by reference to the extent allowed by law for thepurpose of describing and disclosing the compounds and methodologiesreported therein that might be used with the present invention. However,nothing herein is to be construed as an admission that the invention isnot entitled to antedate such disclosure by virtue of prior invention.

THE INVENTION

In one aspect, the present invention provides a composition forpreventing and treating kidney disease and for improving kidneyfunction. The composition comprises at least two ingredients selectedfrom the group consisting of antioxidants and mitochondrial cofactors inamounts sufficient for preventing or treating kidney disease or forimproving kidney function. The invention is based upon the noveldiscovery that kidney function can be altered by administering thecomposition to an animal and that altering kidney function with thecomposition can prevent or treat kidney disease and can improve kidneyfunction, particularly in senior animals. Without being bound by theory,it is believed that composition if effective in preventing and treatingkidney disease because it reduces oxidative stress in an animal.

The composition comprises at least about 100 ppm of one or moreantioxidants and/or at least about 25 ppm of one or more mitochondrialcofactors. The compositions contain antioxidants and mitochondrialcofactors in amounts that are not deleterious to an animal's health,e.g., amounts that do not cause undesirable toxic effects in the animal.In certain embodiments, the composition comprises at least oneingredient that is an antioxidant and at least one ingredient that is amitochondrial cofactor.

Suitable antioxidants and mitochondrial cofactors for use in thecompositions and methods of the present invention include, but are notlimited to, vitamin E, L-carnitine, α-lipoic acid, and vitamin C.Vitamin E can be in any form suitable for consumption by an animalincluding, but not limited to, any tocopherol or tocotrienol compound,any enantiomer or racemate thereof, and any mixture of such compoundshaving vitamin E activity. Vitamin E can be administered as any one or amixture of different forms or in the form of various derivatives thereofsuch as esters, including vitamin E acetate, succinate, palmitate andthe like, that exhibit vitamin E activity after ingestion by an animal.L-carnitine can be administered as such or in the form of any of variousderivatives of carnitine, such as salts, e.g., hydrochloride, fumarateand succinate salts, acetylated carnitine, and the like. α-Lipoic acidcan be administered as such, as a lipoate derivative, for example asdescribed in U.S. Pat. No. 5,621,117, or as a racemic mixture, salt,ester or amide thereof. In one embodiment DL-α-lipoic acid is used.Vitamin C can be administered as ascorbic acid, for example L-ascorbicacid, or as various derivatives thereof such as calcium phosphate salt,cholesteryl salt, and ascorbate-2-monophosphate. Salts of vitamin Cinclude, for example, sodium salt, calcium salt, zinc salt and ferroussalt. Esters include, for example, stearate, palmitate and likederivatives. Vitamin C or a derivative thereof can be in any physicalform, for example, a liquid, a semisolid, a solid, or a heat stable formthat exhibits vitamin C activity after ingestion by the animal. Invarious embodiments, the composition comprises at least two, at leastthree, or all four of vitamin E, vitamin C, L-carnitine and α-lipoicacid.

In another aspect, the present invention provides a food composition forpreventing and treating kidney disease and/or for improving kidneyfunction. The food composition comprises one or more food ingredientsadmixed with antioxidants and mitochondrial cofactors in amountssufficient for preventing or treating kidney disease or for improvingkidney function. Generally, the food composition comprises one or morefood ingredients and at least about 100 ppm of one or more antioxidantsand/or at least about 25 ppm of one or more mitochondrial cofactors. Insome embodiments, the food composition comprises one or more foodingredients and the antioxidants and mitochondrial cofactors in amountsof at least about 500 ppm vitamin E, at least about 40 ppm vitamin C, atleast about 100 ppm L-carnitine, and at least about 25 ppm α-lipoicacid. Preferably, the composition comprises one or more food ingredientsand from about 500 to about 1500 ppm vitamin E, from about 40 to about150 ppm vitamin C, from about 125 to about 400 ppm L-carnitine, and fromabout 25 to about 200 ppm α-lipoic acid. In a feline food, theconcentration of α-lipoic acid, if present, is at least about 25 ppm. Ina canine food, the concentration of α-lipoic acid, if present, is atleast about 50 ppm. In one embodiment the food composition furthercomprises at least about 1% by weight of at least one of tomato pomace,dried spinach, dried carrot, dried citrus pulp, and dried grape pomace.

In certain embodiments, the food composition comprises one or more foodingredients admixed with at least one ingredient that is an antioxidantand at least one ingredient that is a mitochondrial cofactor.

The food ingredients useful in the present invention include any foodingredient suitable for consumption by an animal. Typical foodingredients include but are not limited to fats, carbohydrates,proteins, fibers, nutritional balancing agents such as vitamins,minerals, and trace elements, and mixtures thereof. Skilled artisans canselect the amount and type of food ingredients for a typical food basedupon the dietary requirements of the animal, e.g., the animal's species,age, size, weight, health, and function.

The food ingredient part of the food composition can comprise 100% ofany particular food ingredient of can comprise a mixture of foodingredients in various proportions. In preferred embodiments, the foodcomposition comprises a combination of food ingredients in amounts fromabout 0% to about 50% fat, from about 0% to about 75% carbohydrate, fromabout 0% to about 95% protein, from about 0% to about 40% dietary fiber,and from about 0% to about 15% of one or more nutritional balancingagents.

The Fat and carbohydrate food ingredient is obtained from a variety ofsources such as animal fat, fish oil, vegetable oil, meat, meatby-products, grains, other animal or plant sources, and mixturesthereof. Grains include wheat, corn, barley, and rice.

The protein food ingredient is obtained from a variety sources such asplants, animals, or both. Animal protein includes meat, meatby-products, dairy, and eggs. Meats include the flesh from poultry,fish, and animals such as cattle, swine, sheep, goats, and the like, eatby-products include lungs kidneys, brain, livers, stomachs, andintestines. The protein food ingredient may also be free amino acidsand/or peptides. Preferably, the protein food ingredient comprises meat,a meat by-product, dairy products, or eggs.

The fiber food ingredient is obtained from a variety of sources such asvegetable fiber sources, e.g., cellulose, beet pulp, peanut hulls, andsoy fiber.

The nutritional balancing agents are obtained from a variety of sourcesknown to skilled artisans, e.g., vitamin and mineral supplements andfood ingredients. Vitamins and minerals can be included in amountsrequired to avoid deficiency and maintain health. These amounts arereadily available in the art. The National Research Council (NRC)provides recommended amounts of such nutrients for farm animals. See,e.g., Nutrient Requirements of Swine (10th Rev. Ed., Nat'l AcademyPress, Wash. D.C., 1998). Nutrient Requirements of Poultry (9th Rev.Ed., Nat'l Academy Press. Wash. D.C., 1994), Nutrient Requirements ofHorses (5th Rev. Ed., Nat'l Academy Press, Wash. D.C., 1989). TheAmerican Feed Control Officials (AAFCO) provides recommended amounts ofsuch nutrients for dogs and cats. See American Feed Control Officials,Inc., Official publication, pp. 129-137 (2004). Vitamins generallyuseful as food additives include vitamin A, vitamin B1, vitamin B2,vitamin B6, vitamin B12, vitamin D, biotin, vitamin K, folic acid,inositol, niacin, and pantothenic acid. Minerals and trace elementsuseful as food additives include calcium, phosphorus, sodium, potassium,magnesium, copper, zinc, chloride, iron, selenium, iodine, and iron.

The compositions and food compositions may contain additions ingredientssuch as vitamins, minerals, fillers, palatability enhancers, bindingagents, flavors, stabilizers, emulsifiers, sweeteners, colorants,buffers, salts, coatings, and the like known to skilled artisans.Stabilizers include substances that tend to increase the shelf life ofthe composition such as preservatives, synergists and sequestrants,packaging gases, stabilizers, emulsifiers, thickeners, gelling agents,and humectants. Examples of emulsifiers and/or thickening agents includegelatin, cellulose ethers, starch, starch esters, starch ethers, andmodified starches. Specific amounts for each composition component, foodingredient, and other ingredients will depend on a variety of factorssuch as the particular components and ingredients included in thecomposition; the species of animal; the animal's age, body weight,general health, sex, and diet: the animal's consumption rate; the typeof kidney disease being treated; and the like. Therefore, the componentand ingredient amounts may vary widely and may deviate from thepreferred proportions described herein.

Food compositions may be prepared in a canned or wet form usingconventional food preparation processes known to skilled artisans.Typically, ground animal proteinaceous tissues are mixed with the otheringredients such as fish oils, cereal grains, balancing ingredients,special purpose additives (e.g., vitamin and mineral mixtures, inorganicsalts, cellulose and beet pulp, bulking agents, and the like) and waterin amounts sufficient for processing. These ingredients are mixed in avessel suitable for heating while blending the components. Heating ofthe mixture is effected using any suitable manner, e.g., direct steaminjection or using a vessel fitted with a heat exchanger. Following theaddition of the last ingredient, the mixture is heated to a temperatureof from about 50° F. to about 212° F. Temperatures outside this rangeare acceptable but may be commercially impractical without use of otherprocessing aids. When heated to the appropriate temperature, thematerial will typically be in the form of a thick liquid. The thickliquid is filled into cans. A lid is applied, and the container ishermetically sealed. The sealed can is then placed into conventionalequipment designed to sterilize the contents. Sterilization is usuallyaccomplished by heating to temperatures of greater than about 230° F.for an appropriate time depending on the temperature used, thecomposition, and similar factors. The compositions of the presentinvention can be added to the food compositions before, during, or afterpreparation.

Food compositions may be prepared in a dry form using conventionalprocesses known to skilled artisans. Typically, dry ingredients such asanimal protein, plant protein, grains, and the like are ground and mixedtogether. Moist or liquid ingredients, including fats, oils, animalprotein, water, and the like are then added to and mixed with the drymix. The mixture is then processed into kibbles or similar dry pieces.Kibble is often formed using an extrusion process in which the mixtureof dry and wet ingredients is subjected to mechanical work at a highpressure and temperature and forced through small openings and cut offinto kibble by a rotating knife. The wet kibble is then dried andoptionally coated with one or more topical coatings such as flavors,fats, oils, powders, and the like. Kibble also can be made from thedough using a baking process, rather than extrusion, wherein the doughis placed into a mold before dry-heat processing. The food compositionscan be in the form of a treat using an extrusion or baking processsimilar to those described above for dry food or a toy such as thosedisclosed in U.S. Pat. Nos. 5,339,771 and 5,419,283. The compositions ofthe present invention can be added to the food compositions before,during, or after preparation.

Treats include compositions that are given to an animal to entice theanimal to eat during a non-meal time, e.g., dog bones for canines.Treats may be nutritional wherein the composition comprises one or morenutrients or and may have a food-like composition. Non-nutritionaltreats encompass any other treats that are non-toxic. The composition orcomponents are coated onto the treat, incorporated into the treat, orboth. Treats of the present invention can be prepared by an extrusion orbaking process similar to those used for dry food. Other processes alsomay be used to either coat the composition on the exterior of existingtreat forms or inject the composition into an existing treat form.

All weights and concentrations for the compositions of the presentinvention are based on dry weight of a composition after all componentsand ingredients are admixed.

In another aspect, the present invention provides the compositions andfood compositions of the present invention further comprising one ormore renal drugs. Renal drugs useful in the invention are any renaldrugs known to skilled artisans to be useful for combating kidneydisease. Preferred drugs include lysosome-activating compounds such asthose described in U.S. Pat. No. 6,589,748, triterpene saponins such asthose described in U.S. Pat. No. 6,784,159, activin inhibitors such asthose described in U.S. Pat. No. 6,599,876 and US Patent ApplicationNumber (USPAN) 20020028762, integrin receptor inhibitors and TGFinhibitors such as those described in U.S. Pat. No. 6,492,325, TGFactivation inhibitors such as those described in U.S. Pat. No.6,458,767, and insulin-like growth factor (IGF) as described in U.S.Pat. No. 5,723,441. Most Preferred drugs include Converting Enzyme (ACE)inhibitors, androgens, erythropoiten, and calcitriol. Angiotensin andendothelin are potent systemic vasoconstrictors with specific intrarenaleffects that contribute to progressive renal injury. A variety of renaldrugs are used to mitigate the effect of these vasoconstrictors.Angiotensin converting enzyme inhibitors (enalapril—Enacard and Vasotecand benazepril—Lotensin) have been associated with a reduction in theseverity of proteinuria and slowing of progression of renal failure. TheACE inhibitor enalapril (Enacard, Vasotec) limits glomerular andsystemic hypertension, proteinuria, and glomerular andtubulointerstitial lesions. Angiotensin blockers and endothelininhibitors have beneficial effects in renal disease. Vasopeptideinhibitors are agents that inhibit both ACE and neutral endopeptidase,an enzyme involved in the breakdown of natriuretic peptides,adrenomedullin, and bradykinin. These renal drugs decrease angiotenin IIproduction and increase accumulation of vasodilators. Renal animals withsystemic hypertension respond to calcium channel blockers such asamlodipine (Norvasc). Uremic gastritis (esophagitis, gastritis, gastriculceration and hemorrhage) is treated with H2 receptor antagonists(cimetidine—Tagamet, famotidine—Pepcid), proton pump blockers(omeprazole—Prilosec), cytoprotective agents (misoprostol—Cytotec), andantiemetic drugs that effect the emetic center(chlorprornazine—Thorazine, perchlorperazine—Compazine,metoclopramide—Reglan). Androgens or anabolic steroids (Stanozol,Winstrol-V) are used in the treatment of anemia associated with chronicrenal failure. Hormone replacement therapy using recombinant human (orother species) erythropoiten (Epoetin alpha, Epogen, Procrit) is thetreatment of choice for severe anemia associated with renal failure.Phosphate binders (aluminum hydroxide—Amphojel, aluminumcarbonate—Basaijel) are used to control hyperphosphatemia and secondaryrenal hyperparathyroidism. Calcitriol (1,25-dihydroxycholecalciferol)(Rocaltrol) and vitamin D analogues cause a calcium-independentsuppression of parathyroid hormone (PTH). Administration of phosphatebinders, calcitriol and related compounds has been advocated in chronicrenal failure to prevent multi-system toxicity caused by PTH. Potassiumdepletion and hypokalemia are common in cats with chronic renal failure.Oral supplementation of potassium in the form of potassium gluconate(Tumil K, RenaKare, Kolyum) or citrate is recommended. Holistic renaldrugs and compositions are also included in the present invention.Preferred holistic renal drugs include cranberry extract and mannose.Cranberry extract is purported to reduce the prevalence of urinary tractinfection which is a common risk factor for long-term decline of renalfunction. Renal drugs include typical small molecule pharmaceuticals,small proteins, macromolecular proteins and molecules, and antibodiesand further include vaccines designed to prevent renal disease.Antibodies include polyclonal and monoclonal antibodies andimmunoglobulin fragments such as Fv, Fab, Fab′, F(ab′)2, or otherantigen-binding antibody subsequences that interact with an antigen andperform the same biological function as a native antibody. The renaldrugs are administered to the animal using any method appropriate forthe renal drug and in amounts known to skilled artisans to be sufficientto treat or prevent renal disease.

In a further aspect, the present invention provides methods forpreventing and treating kidney disease and/or for improving kidneyfunction. One method comprises administering in conjunction a kidneydisease preventing or treating amount of a composition comprising atleast two ingredients selected from the group consisting of antioxidantsand mitochondrial cofactors. The method is particularly applicable toanimals that are susceptible or suffering from kidney disease caused byaging, xenobiotics, or pathogens. In another aspect, the inventionprovides methods for improving kidney function by administering a kidneyfunction improving amount of the composition to an animal. The method isparticularly applicable to aging and senior animals that areexperiencing a decline in kidney function due to aging. Other methodsfor accomplishing these aspects of the invention comprise administeringthe composition in conjunction with a food composition comprising one ormore food ingredients. In a preferred embodiment, the composition andthe food ingredients are administered in a food composition comprisingan admixture of the composition and the food ingredients. In preferredembodiments, the animal is a feline or a canine. In one embodiment, theanimal is a companion animal such as working dogs, farm cats kept forrodent control, pet dogs, and pet cats. In another embodiment, theanimal is a senior animal. In certain embodiments, the methods compriseadministering to the animal a composition wherein at least oneingredient is an antioxidant and at least one ingredient is amitochondrial cofactor. The methods are beneficial for decreasing theamount of albumin in the urine of senior and other animals. A moderateincrease in albumin in the urine, or microalbuminuria, is considered tobe an early indicator of renal glomerular disease. Without being boundby any particular theory, it is believed that the benefits describedabove result from physiological effects of the addition of antioxidantsand/or mitochondrial cofactors to animal diets, particularly senioranimal diets, and that these effects are related to mitigation of theproduction of, and the damage caused by, toxic free radicals. Themethods slow, arrest, or reverse age-related decline in kidney function.Such effects are considered to improve kidney function.

In one embodiment, the method comprises administering to an animal,particularly a senior animal, a food composition comprising at leastabout 500 ppm, for example about 500 to about 1500 ppm, vitamin E; atleast about 100 ppm, for example about 125 to about 400 ppm,L-carnitine; at least about 25 ppm, for example about 25 to about 200ppm, α-lipoic acid; and at least about 40 ppm, for example about 40 toabout 150 ppm, vitamin C. Such a composition optionally furthercomprises at least about 1% by weight of at least one of tomato pomace,dried spinach, dried carrot, dried citrus pulp, and dried grape pomace.

The compositions are administered to the animal using any suitablemethod, preferably by feeding the compositions to the animal.

The methods are accomplished by administering the compositions to theanimal in various forms. For example, one or more composition componentsand food ingredients are in separate containers and admixed just priorto administration. In one embodiment, the antioxidants and mitochondrialcofactors are admixed in one container and the resulting compositionmixed with food ingredients just prior to administration, e.g., bystirring the composition into or sprinkling the composition onto thefood ingredients. In another, one or more of the composition componentsare admixed with the food ingredients during manufacture and theremaining composition components admixed with such food ingredients justprior to administration. In a further, the composition is a component ofa pour-on formulation (preferably containing vitamins and minerals) thatis applied to food ingredients prior to administration. In another, thecomposition is admixed with one or more food ingredients and suchadmixture is mixed with other food ingredients before administration. Ina further, the composition is coated onto the food ingredients duringthe manufacturing process or after the food composition is manufactured.In another, the composition is administered orally and the foodcomposition is fed to the animal.

The composition is administered orally using any suitable form for oraladministration, e.g., tablets, pills, suspensions, solutions (possiblyadmixed with drinking water), emulsions, capsules, powders, syrups, andpalatable feed compositions (a confectionery for a human or a treat orflavored treat for an animal). In a preferred embodiment, thecomposition components and the food ingredients are admixed duringmanufacture process used to prepare the food composition suitable foradministration in the form of a food for consumption by the animal.

A further method comprises administering the composition or foodcomposition of the present invention in conjunction with one or morerenal drugs. Typically, health care professionals, e.g., doctors andveterinarians, diagnose kidney disease in an animal and prescribe arenal drug (any drug useful to prevent or treat kidney disease in ananimal) to treat the disease. The animal is administered the renal druguntil the symptoms cease and the disease is considered cured. Generally,the renal drug is not administered after the disease is consideredcured. Administration of the renal drug is resumed only if the animalhas a reoccurrence of the kidney disease. In the present invention thecompositions and renal drugs are administered in conjunction to theanimal during treatment. After administration of the renal drug ceases,the compositions are administered to the animal to prevent reoccurrenceof the disease. In another embodiment, the compositions are administeredto the animal only after use of the renal drug is discontinued toprevent disease reoccurrence.

Any suitable diagnostic method of assessing kidney function can be usedto determine whether an improvement occurs. In one embodiment, kidneyfunction is assessed by the level(s) of one or more biomarkers in atissue or biofluid sample. A particularly useful diagnostic methodherein comprises measurement of albumin content of urine. Elevatedalbumin levels in urine, in particular the slightly to moderatelyelevated levels known as microalbuminuria, are an indicator of a declinein kidney function as occurs, for example, in incipient kidney disease.

In a further aspect, the present invention provides a kit foradministering a kidney disease preventing or treating amount of acomposition or a kidney function improving amount of a composition to ananimal comprising in separate containers in a single package at leastone ingredient selected from the group consisting of antioxidants andmitochondrial cofactors and at least one different ingredient selectedfrom the group consisting of antioxidants and mitochondrial cofactors.

In one embodiment, the kit further comprises one or more foodingredients in a separate package. In this embodiment, the compositionor individual composition components are admixed with the foodingredients just prior to administering the resulting admixture to ananimal. Generally, the kits contain the composition components inamounts sufficient to supply to an animal at least about 100 ppm of oneor more antioxidants and/or at least about 25 ppm of one or moremitochondrial cofactors. In one embodiment, the kit contains at leastabout 500 ppm vitamin E, at least about 40 ppm vitamin C, at least about100 ppm L-carnitine, and at least about 25 ppm α-lipoic acid.

In other embodiments, the kits further comprise one or more renal drugsin a separate package.

In other embodiments, the kits further comprise one or more renaldiagnostic devices for determining kidney function and evaluating thepresence and severity of kidney disease in an animal in a separatepackage. The renal diagnostic devices useful in the present inventioninclude any device suitable for determining kidney function andevaluating the presence and severity of kidney disease in an animal.Preferred diagnostic methods include serum urea nitrogen (SUN),creatinine levels, urine specific gravity, and DNA damage, includingurine assays for albumin such as those described in U.S. Pat. No.6,589,748, U.S. Pat. No. 6,447,989 and USPAN 20050026225 and comet trailassays. Diagnostic methods arc based upon known techniques including (1)blood markers such as elevated blood urea nitrogen concentration,elevated serum creatinine concentration, hyperphosphatemia, hyperkalemiaor hypokalemia, metabolic acidosis and hypoalbuminemia, (2) urinemarkers such as impaired urine concentrating ability, proteinuria,cylinduria, renal hematuria, inappropriate urine pH, inappropriate urineglucose concentration, and cystinuria, (3) physical, imaging, anddiagnostic markers such as size, shape, location, and density, (4)single nucleotide polymorphisms (SNPs) such as those disclosed in WO2004113570 A2, (5) genetic profiles that are indicative of kidneydisease, (6) proteomic profiles that are indicative of kidney disease,and (7) metabolic profiles that are indicative of kidney disease. Thesediagnostic methods and devices (e.g., test strips. ELISA assays, cometassays,) based upon such methods are commonly available to skilledartisans such as scientists and health care professionals and many areavailable to consumers, e.g., the Heska Corporation's (Fort CollinsColo.) E.R.D.—HealthScreen Urine Tests that detects small amounts ofalbumin in the urine (“microalbuminuria”).

In other embodiments, the kits further comprise information that the useof the compositions and methods of the present invention will prevent ortreat kidney disease or improve kidney function.

The kits of the present invention contain the compositions, compositioncomponents, food compositions, food ingredients, renal drugs, and renaldiagnostic devices in any of various combinations. For example, one kitcomprises a food composition comprising an admixture of one or more foodingredients and the composition in combination with a renal diagnosticdevice or a renal drug or both. Another kit contains the compositioncomponents in separate packages and one or more food ingredients in oneor more separate packages with or without renal drugs or renaldiagnostic devices in separate packages. Numerous such combinations canbe constructed by the skilled artisan.

In another aspect, the present invention provides a means forcommunicating information about or instructions for admixing andadministering one or more of the compositions, composition components,food compositions, food ingredients, and renal drugs and informationabout or instructions for using the renal diagnostic devices of thepresent invention. The communicating means comprises a document, digitalstorage media, optical storage media, audio presentation, or visualdisplay containing the information or instructions. Preferably, thecommunication is a displayed web site or a brochure, product label,package insert, advertisement, or visual display containing suchinformation or instructions. Useful information includes one or more of(1) methods and techniques for combining and administering thecompositions, composition components, food compositions, foodingredients, and renal drugs, (2) information for using the renaldiagnostic devices, (3) details about the side effects, if any, causedby using the present invention in combination with other drugs, and (4)contact information for animals to use if they have a question about theinvention and its use. Useful instructions include dosages,administration amounts and frequency, and administration routes. Thecommunication means is useful for instructing an animal on the benefitsof using the present invention and communicating the approved methodsfor administering the invention to an animal.

The compositions, methods, and kits are useful for decreasing themorbidity and mortality for animals susceptible to or suffering fromkidney disease and for improving kidney function, particularly in agingand senior animals.

EXAMPLES

This invention can be further illustrated by the following examples ofpreferred embodiments thereof, although it will be understood that theseexamples are included merely for purposes of illustration and are notintended to limit the scope of the invention unless otherwisespecifically indicated.

Example 1

Urine samples from 48 senior dogs, all greater than 8 years of age, werefirst analyzed for albumin content using a microalbuminuria test kitcommercially available from Heska Corporation, Fort Collins, Colo. Thedogs were then separated into two groups, a control group and a testgroup, having 24 dogs each. The control group was fed, for a minimum ofone year, a food formulated to meet AAFCO recommendations for nutrientintake for adult dogs as their sole nutrition source. The test group wasfed, for a minimum of one year, a fortified but otherwise substantiallyidentical, food having enhanced levels of vitamin E, vitamin C,L-carnitine and DL-α-lipoic acid. Additionally, the fortified foodcontained 1% tomato pomace, 1% dried spinach, 1% dried carrot, 1% driedcitrus pulp and 1% dried grape pomace. The ingredients of the controland fortified foods were identical, except as described in Table 1. Thetomato pomace, dried spinach, dried carrot, dried citrus pulp and driedgrape pomace in the fortified food replaced corn used in the controlfood.

TABLE 1 Compositions of Control and Fortified Foods Ingredient ControlFortified Vitamin E about 100 ppm about 1000 ppm L-carnitine None addedabout 260 ppm DL-α-lipoic acid None added about 120 ppm Vitamin C Noneadded about 80 ppm Tomato pomace None added 1% Dried spinach None added1% Dried carrot None added 1% Dried citrus pulp None added 1% Driedgrape pomace None added 1%

After at least one year, urine samples were taken from each of the dogsand tested for albumin. One dog from the control group was lost tofollow-up during the study. If a sample was not available after at leastone year, the next available sample was taken either prior to (in casesof dogs that died prior to one year) or after that time point (no morethan six months separation).

The Heska microalbuminuria assay tests for presence of albumin at verylow concentrations in the urine, and, as noted above, microalbuminuriais considered to be an early indicator of renal glomerular disease.Results are read as categories (none, mild, moderate, severe) against acolor scale.

The dogs that were fed the control food, without enhanced levels ofantioxidants or mitochondrial cofactors, were more likely to worsen inseverity of renal microalbuminuria than the dogs that were fed the testfood. A total of 9 animals out of 23 in the control group, but only 5 of24 animals in the test group worsened in severity. Further, 3 animals inthe test group actually exhibited a decrease in severity, whereas only 1animal in the control group exhibited such a decrease.

Further, as shown in Table 2, fully 50% of the control animals that werein the normal range pre-test tested in a non-normal range post-test, asanalyzed using a McNemar test. In the test group, only 23% of theanimals testing in the normal range pre-test tested in the non-normalrange post-test.

TABLE 2 McNemar Test Results Control group Test group Pre-test 8 normal13 normal 16 non-normal 11 non-normal Post-test 4 normal 10 normal 19non-normal 14 non-normal

In the specification, there have been disclosed typical preferredembodiments of the invention and, although specific terms are employed,they are used in a generic and descriptive sense only and not forpurposes of limitation, the scope of the invention being set forth inthe following claims. Obviously many modifications and variations of thepresent invention are possible in light of the above teachings. It istherefore to be understood that within the scope of the appended claimsthe invention may be practiced otherwise than as specifically described.

1-8. (canceled)
 9. A method for preventing or treating kidney disease orfor improving kidney function comprising administering a kidney diseasepreventing or treating amount or a kidney functioning improving amountof at least two ingredients selected from the group consisting ofantioxidants and mitochondrial cofactors to an animal.
 10. The method ofclaim 9 wherein the ingredients comprise vitamin E, L-carnitine,α-lipoic acid, and vitamin C.
 11. The method of claim 10 wherein theingredients comprise at least about 500 ppm vitamin E, at least about100 ppm L-carnitine, at least about 25 ppm α-lipoic acid, and at leastabout 40 ppm vitamin C.
 12. The method of claim 9 further comprisingadministering the composition to the animal in conjunction with one ormore renal drugs.
 13. The method of claim 9 further comprisingadministering the composition to the animal in conjunction with one ormore food ingredients.
 14. The method of claim 13 wherein the foodingredients and the antioxidants and/or mitochondrial cofactors areadministered in a food composition comprising an admixture of the foodingredients and the antioxidants and/or mitochondrial cofactors.
 15. Themethod of claim 13 further comprising administering the composition tothe animal in conjunction with one or more renal drugs.
 16. The methodof claim 13 wherein the composition is admixed with the food ingredientjust prior to feeding the mixture to the animal.
 17. The method of claim13 wherein the composition is admixed with the food ingredient duringthe manufacturing process used to prepare the food composition.
 18. Themethod of claim 13 wherein the food ingredient is selected from thegroup consisting of fats, carbohydrates, proteins, fibers, nutritionalbalancing agents, and mixtures thereof.
 19. The method of claim 9wherein the animal is a senior animal.
 20. The method of claim 9 whereinthe animal is feline or canine.
 21. The method of claim 9 wherein atleast one ingredient is an antioxidant and at least one ingredient is amitochondrial cofactor. 30-31. (canceled)